Adipose tissue exerts a powerful effect on glucose metabolism by regulating the concentration of circulating adiponectin (Goldline et al., Lancet 362:1431 (2003)). High adiponectin in the lean state is linked to elevated insulin sensitivity whereas low adiponectin in the obese state is linked to insulin resistance and diabetes (Arita et al., Biochem. Biophys. Res. Commun. 257:79 (1999); Hotta et al., Artererioscler. Thromb. Vase. Biol. 20:1595 (2000); Maeda et al., Diabetes 50:2094 (2001); Weyer et al., J. Clin. Endocrinol. Metab. 2001, 86:1930 (2001)). Endogenous glucose production is elevated in diabetes (Wahren et al., Annu. Rev. Nutr. 27:329 (2007)). Studies in mice and liver cells show that adiponectin lowers glucose production by increasing the insulin sensitivity of the liver (Berg et al., Nat. Med. 7:947 (2001); Combs et al., J. Clin. Invest. 108:1875 (2001); Combs et al., Endocrinology 145:367 (2004)).
The signal transduction pathway of adiponectin is currently linked to (a) adiponectin receptors that bind to the full-length or the carboxy-terminal ‘globular’ fragment of adiponectin, (b) binding of the intracellular domains of adiponectin receptors 1 and 2 to the adaptor APPL1 and (c) the activation of AMPK, a signaling intermediate that reduces the gene expression of rate limiting enzymes for glucose production (Combs et al., J. Clin. Invest. 108:1875-(2001); Combs et al., Endocrinology 145:367 (2004); Tomas et al., Proc. Natl. Acad. Sci. USA 99:16309 (2002); Yamauchi et al., Nat. Med. 8:1288 (2002); Shklyaev et al., Proc. Natl. Acad. Sci. USA 100:14217 (2003); Nawrocki et al., J. Biol. Chem. 281:2654 (2006); Andreelli et al., Endocrinology 147:2432 (2006); Mao et al., Nat. Cell Biol. 8:516 (2006); Brooks et al., J. Biol. Chem. 282:35069 (2007); Yoon et al., Exp. Mol. Med. 41:577 (2009); Wang et al., J. Biol. Chem. 282:7991 (2007)). However, the inhibition of glucose production by this pathway is not completely clear.
Glucose production depends on autophagy, a regulated mechanism of intracellular degradation that is inhibited by insulin (Amherdt et al., J. Clin. Invest. 54:188 (1974)). Autophagy provides the biochemical intermediates for glucose production through the hydrolysis of proteins, glycogen and triglycerides (Mortimore et al., Annu. Rev. Nutr. 7:539 (1987); Kotoulas et al., Pathol. Res. Pract. 202:631 (2006); Singh et al., Nature 458:1131 (2009)). Insulin inhibition of autophagy in isolated hepatocytes is linked to the activation of mTOR (Blommaart et al., J. Biol. Chem. 270:2320 (1995); Kanazawa et al., J. Biol. Chem. 279:8452 (2004)). Hence, reports that AMPK, an essential mediator of adiponectin action, inhibits mTOR and stimulates autophagy are perplexing (Shaw et al., Cancer Cell 6:91 (2004); Meley et al., J. Biol. Chem. 281:34870 (2006); Xu et al., Cell Death Differ. 14:1948 (2007); Liang et al., Nat. Cell Biol. 9:218-(2007); Meijer et al., Autophagy 3:238 (2007); Cheng et al., J. Biol. Chem. 279:15719 (2004); Hoyer-Hansen et al., Mol. Cell. 25:193 (2007)).
The present invention addresses previous shortcomings in the art by providing a novel polynucleotide and polypeptide that connects insulin, adiponectin, and glucose production and that can be used for diagnostic and therapeutic methods.